Abstract
Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8+ T cells1. Previously, two distinct populations of antigen-experienced CD8+ T cells, termed effector (TEFF) and central memory (TCM) cells, have been described2,3,4,5. After adoptive transfer into CD8-deficient mice, TEFF, but not TCM, cells restored AHR, eosinophilic inflammation and IL-13 levels. TEFF, but not TCM, cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred TEFF cells were a source of IL-13. These data suggest an important role for effector CD8+ T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.
Similar content being viewed by others
References
Miyahara, N. et al. Contribution of antigen-primed CD8+ T cells in the development of airway hyperresponsiveness and airway inflammation is associated with IL-13. J. Immunol. 172, 2549–2558 (2004).
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).
Weninger, W., Crowley, M.A., Manjunath, N. & von Andrian, U.H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).
Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).
Busse, W.W. & Lemanske Jr., R.F. Asthma. N. Engl. J. Med. 344, 350–362 (2001).
Oshiba, A. et al. Modulation of antigen-induced B and T cell responses by antigen-specific IgE antibodies. J. Immunol. 159, 4056–4063 (1997).
De Sanctis, G.T. et al. T-lymphocytes regulate genetically determined airway hyperresponsiveness in mice. Nat. Med. 3, 460–462 (1997).
Robinson, D.S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).
Gonzalez, M.C. et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma. Relative increases in OKT8 cells in single early responders compared with those in late-phase responders. Am. Rev. Resp. Dis. 136, 600–604 (1987).
O'Sullivan, S. et al. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am. J. Resp. Crit. Care Med. 164, 560–564 (2001).
Hamelmann, E. et al. Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a murine model of airway sensitization. J. Exp. Med. 183, 1719–1729 (1996).
Swanson, B.J., Murakami, M., Mitchell, T.C., Kappler, J. & Marrack, P. RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process. Immunity 17, 605–615 (2002).
Ott, V.L., Cambier, J.C., Kappler, J., Marrack, P. & Swanson, B.J. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat. Immunol. 4, 974–981 (2003).
Takeda, K. et al. Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice. J. Exp. Med. 186, 449–454 (1997).
Tomkinson, A. et al. Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbumin-sensitized mice. Am. J. Respir. Crit. Care Med. 163, 721–730 (2001).
Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).
Hoshino, T., Winkler-Pickett, R.T., Mason, A.T., Ortaldo, J.R. & Young, H.A. IL-13 production by NK cells: IL-13-producing NK and T cells are present in vivo in the absence of IFN-γ. J. Immunol. 162, 51–59 (1999).
Akbari, O. et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9, 582–588 (2003).
Burd, P.R., Thompson W.C., Max, E.E. & Mills, F.C. Activated mast cells produce interleukin 13. J. Exp. Med. 181, 1373–1380 (1995).
Grunstein, M.M. et al. IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L520–L528 (2002).
Watanabe, A. et al. Transfer of allergic airway responses with antigen-primed CD4+ but not CD8+ T cells in brown Norway rats. J. Clin. Invest. 96, 1303–1310 (1995).
Fung-Leung, W.P., Schilham, M.W. & Rahemtulla, A. CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell 65, 443–449 (1991).
Fabien, N., Bergerot, I., Maguer-Satta, V., Orgiazzi, J. & Thivolet, C. Pancreatic lymph nodes are early targets of T cells during adoptive transfer of diabetes in NOD mice. J. Autoimmun. 8, 323–334 (1995).
Oshiba, A. et al. Passive transfer of immediate hypersensitivity and airway hyperresponsiveness by allergen-specific immunoglobulin (Ig) E and IgG1 in mice. J. Clin. Invest. 97, 1398–1408 (1996).
Acknowledgements
We thank J. Cambier, P. Marrack and J. Kappler for support; J.J. Lee for the antibody to major basic protein; and L.N. Cunningham and D. Nabighian for assistance. This work was supported by National Institute of Health grants HL-36577, HL-61005 and AI-42246 and Environmental Protection Agency grants R825702 (E.W.G.) and AI-52225.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Preferential treatment of TEFF in the lung (PDF 153 kb)
Supplementary Fig. 2
Quantitation of TEFF or TCM in the lung sections from the submucosal tissue around the major airways or peripheral tissue. (PDF 20 kb)
Supplementary Fig. 3
Histograms of CFSE-labeled TEFF and TCM prior to transfer and following recovery from the lungs and PBLN, respectively, of sensitized and challenged CD8-deficient mice. (PDF 23 kb)
Supplementary Fig. 4
Intracellular staining for IL-4, IL-5, IL-13, and IFN-γ in CD8+ T cells from OVA sensitized and challenged recipient CD8-deficient mice following transfer of TCM. (PDF 22 kb)
Rights and permissions
About this article
Cite this article
Miyahara, N., Swanson, B., Takeda, K. et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat Med 10, 865–869 (2004). https://doi.org/10.1038/nm1081
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1081
- Springer Nature America, Inc.
This article is cited by
-
Type-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations
Nature Communications (2023)
-
Clinical implications of CD4+ T cell subsets in adult atopic asthma patients
Allergy, Asthma & Clinical Immunology (2018)
-
Synergistic activation of pro-inflammatory type-2 CD8+ T lymphocytes by lipid mediators in severe eosinophilic asthma
Mucosal Immunology (2018)
-
Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma
Respiratory Research (2017)
-
CD4+ and CD8+ T cells play a central role in a HDM driven model of allergic asthma
Respiratory Research (2016)